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Human herpesvirus 8-related diseases: Histopathologic diagnosis and disease mechanisms
Author’s Accepted Manuscript Human Herpesvirus 8-Related Histopathologic Diagnosis and Mechanisms
Diseases: Disease
Matthew Auten, Annette S. Kim, Kyle T. Bradley, Flavia G. Rosado www.elsevier.com/locate/serndb
PII: DOI: Reference:
S0740-2570(17)30045-X http://dx.doi.org/10.1053/j.semdp.2017.04.004 YSDIA50506
To appear in: Seminars in Diagnostic Pathology Cite this article as: Matthew Auten, Annette S. Kim, Kyle T. Bradley and Flavia G. Rosado, Human Herpesvirus 8-Related Diseases: Histopathologic Diagnosis and Disease Mechanisms, Seminars in Diagnostic Pathology, http://dx.doi.org/10.1053/j.semdp.2017.04.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Human Herpesvirus 8-Related Diseases: Histopathologic Diagnosis and Disease Mechanisms
Matthew Autena1, Annette S. Kimb2, Kyle T. Bradleyc3, Flavia G. Rosadod* a
Department of Pathology, West Virginia University Department of Pathology, Brigham and Women's Hospital c Department of Pathology & Laboratory Medicine, Emory University Hospital, 1364 Clifton Rd NE, Atlanta, GA 30322 d Department of Pathology, West Virginia University, Address: 1 Medical Center Dr, Room 2146F/HSC North [email protected] [email protected] [email protected] [email protected] * Corresponding author. Phone: 304-293-0288; Fax: 304-293-1627. b
ABSTRACT The emergence of HIV/AIDS more than three decades ago led to an increased incidence of diseases caused by HHV8 co-infection, particularly Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Over time, the development of highly effective AIDS therapies has resulted in a decreased incidence of HHV8-associated entities, which are now more commonly found in patients with undiagnosed and/or untreated AIDS. Due to their rarity, some of these diseases may be difficult to recognize without appropriate clinical information. This article provides an overview of HHV8-related disorders, with a focus on their morphologic and phenotypic features, and includes a brief overview of laboratory methods used 1
Phone: 304-293-1621; Fax: 304 293 1627
2
Phone: 617-525-3172; Fax: 617-264-5169
3
Phone: 404-712-4066; Fax: 404-712-5596 1
to detect HHV8. Disease mechanisms by which the HHV8 virion promotes tumorigenesis are also reviewed.
Keywords: HHV8, AIDS, Kaposi, Primary effusion lymphoma, Castleman
[MANUSCRIPT] At the peak of the acquired immune deficiency syndrome (AIDS) epidemic, the analysis of samples of Kaposi sarcoma (KS) revealed a novel virus called Kaposi sarcoma-associated herpesvirus, currently known as human herpesvirus 8 (HHV8).1 Since its initial discovery, HHV8 infection has been linked to the pathogenesis of other neoplastic and non-neoplastic diseases, such as primary effusion lymphoma (PEL) and the plasma cell variant of Castleman disease. 1-3 Although more prevalent in the setting of AIDS, HHV8-related disorders also occur in human immunodeficiency virus (HIV)-negative individuals that are otherwise immunocompromised, e.g., due to immunosuppressive therapy or age-related immune senescence.4
Given their rarity and relatively non-descript morphologic features, the histopathologic diagnoses of HHV8 related diseases typically requires a high index of suspicion. A positive history of HIV infection is helpful but may not be known or available at the time of initial presentation. This review article provides an overview of HHV8-related diseases, with focus on the histopathologic diagnosis, ancillary diagnostic methods, and disease mechanisms.
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Epidemiology
HHV8 was first described in 1994 as a herpesvirus homologous to Epstein-Barr virus (EBV).1 It belongs to the subfamily of gamma herpesviruses, and is the only member of the genus rhadinovirus known to infect humans.5
The prevalence of HHV8 infection varies widely according to geographic distribution, age, and behavioral groups, mirroring that of AIDS. It ranges from 1-25% in North America and Europe, 4,6,7
and is as high as 80% in Africa.4 In HIV-negative individuals, seroprevalence steadily
increases for each decade of life after 30 years of age.8 In adults, it is higher in homosexual individuals, drug abusers, and commercial sex workers.8
The route of transmission of HHV8 is largely unknown. HHV8 genetic material has been identified in variable proportions in oropharyngeal epithelium, saliva, semen, and blood, but the exact mechanism of transmission is not entirely understood. While the predominant form of transmission is sexual, the detection of HHV8 seroconversion in children suggests the existence of non-sexual routes. Although viral material has been detected in blood components, bloodborne transmission is rare.8
Although primary infections are likely asymptomatic in most cases, reported manifestations include febrile maculopapular rash in children,9 and a variety of non-specific symptoms such as fever, fatigue, lymphadenopathy, diarrhea, and cutaneous rash in adults.10 Severe forms of 3
primary infection, manifesting as bone marrow aplasia, fever and plasmacytosis, have been reported in organ transplant recipients.8
Clinical and Histopathologic Features HHV-8 infection is associated with Kaposi sarcoma, plasma cell variant of Castleman disease (more frequently the multicentric type), germinotropic lymphoproliferative disorder, primary effusion lymphoma (including extracavitary variant) and large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease. The clinical, morphologic and phenotypic features of these diseases are discussed below and summarized in Table 1 and Figures A-F. Kaposi Sarcoma Originally described in 1872,11 Kaposi sarcoma (KS) is a low grade neoplasm of HHV8-infected endothelial cells that arises in skin, lymph nodes, and gastrointestinal tract or other viscera, typically in elderly or immunocompromised patients.4 There are four epidemiologic forms of KS, all of which are histologically and phenotypically similar: (1) sporadic or classic, seen primarily in elderly men of Jewish or Mediterranean heritage; (2) endemic, seen in areas of central Africa; (3) iatrogenic, arising secondary to immunosuppressive therapy; and (4) AIDSrelated.12 Clinically, cutaneous KS tends to progress from early violaceous patches to more advanced lesions (plaques) and ultimately nodules (tumor).12 Other clinical variants described are infiltrative, ecchymotic, telangiectatic, keloidal, and cavernous/lymphangioma-like.13-17
4
Histologically, the cellular components of KS vary with the stage of disease.4 Patch lesions are defined by dermal proliferations of vascular spaces composed of irregular endothelial cells alongside normal capillaries. In plaques, the sheets or fascicles of spindle cells appear and begin to encircle the vascular space. Finally, in nodular lesions, the spindle cells predominate forming large fascicles.18
Immunohistochemical techniques using antibodies that target the HHV8 latency-associated nuclear antigen-1 (LANA-1) are positive in almost all cases,19 and are useful to confirm the diagnosis of KS. The tumor spindle cells express vascular markers CD31, CD34, FLI-1, FVIII, actin, von Willebrand factor, VEGRFR-3, and D2-40, regardless of HIV status.18,20,21 Highlyspecific PCR for HHV8 DNA sequences show a sensitivity of 86-100%, tending to be lower in classic KS compared to AIDS-related KS.22
Multicentric Castleman Disease Castleman disease, also known as angiofollicular lymphoid hyperplasia, was first described in 1956 by Benjamin Castleman, who studied biopsies from patients with bulky mediastinal lymphadenopathy.23,24 It is a heterogeneous group of inflammatory lymphadenopathies divided clinically into unicentric and multicentric variants based on the anatomic distribution of disease, and encompassing the hyaline-vascular and plasma cell morphologic variants.25 Unicentric disease typically corresponds to the hyaline-vascular morphologic variant whereas multicentric disease typically corresponds to the plasma cell variant, but the associations are imperfect.
5
Multicentric Castleman disease (MCD) is a syndrome characterized clinically by cyclic episodes of B-symptoms (fever, night sweats, and weight loss), hepatosplenomegaly, and lymphadenopathy, frequently abdominal or mediastinal. In some cases, skin rashes, body cavity effusions and neurologic symptoms are also seen.26-28 Common laboratory abnormalities include elevated erythrocyte sedimentation rate, anemia, thrombocytopenia, polyclonal hypergammaglobulinemia, hypoalbuminemia, elevated serum levels of IL-6, LDH, and Creactive protein.26-28
AIDS patients classically develop MCD,29 in which HHV8 DNA can be detected in nearly 100% of cases.30 There is high frequency of concurrent Kaposi sarcoma,30,31 and approximately 20% of these patients go on to develop primary effusion lymphoma or HHV8-positive large B-cell lymphoma.32 Despite the strong association of MCD and AIDS, HHV8 positivity is also seen in approximately 40% of AIDS-unrelated cases of MCD. In addition, HHV8-negative “idiopathic” forms of MCD have been recognized.33 Interestingly, HHV8-positive MCD is also associated with POEMS (P-polyneuropathy, O-organomegaly, E-endocrinopathy, M-monoclonal gammopathy, S- skin changes) syndrome.34
HHV8-positive cases of Castleman disease are usually plasma cell variant, which is morphologically characterized by variable degree of follicular involution, interfollicular vascular proliferation and polyclonal plasmacytosis, with a variable numbers of polyclonal plasmablasts.27 Plasmablasts, when present, are usually found in the mantle zones of the follicles, and it is these cells that are selectively infected with HHV8 and stain positive using LANA-1 immunohistochemistry. Cases with large number of plasmablasts have been named
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“plasmablastic variant” in the literature.25 Nodules of plasmablasts in the interfollicular space or within germinal centers may develop as the disease progresses, and have been termed “microlymphomas.”35 In these cases a number of IgM lambda-restricted, HHV8-positive plasmablasts have been identified and are thought to represent an intermediate stage in the progression from MCD to frank HHV8-positive large B-cell lymphoma.35 Despite the lambda restriction of the plasmablasts, immunoglobulin gene rearrangement studies are polyclonal.36 In contrast, HHV8-negative forms of plasma cell variant of Castleman disease, tend to show a more mature proliferation of plasma cells that respect the mantle zones of the adjacent follicles. By immunohistochemistry, plasma cells can be highlighted with CD138 or CD79a, and the intact follicular architecture can be demonstrated by follicular dendritic cell markers such as CD21 or CD23. Plasma cells are polytypic with kappa and lambda, and comprise a mixture of heavy chains IgG, IgM and IgA.37
Patients with MCD are treated systemically with chemotherapy and steroids, and the prognosis is generally poor.38 In contrast, unicentric Castleman disease presents as localized lymphadenopathy in otherwise asymptomatic patients, and is usually successfully treated with surgical excision.39
Germinotropic lymphoproliferative disorder
Germinotropic lymphoproliferative disorder is a monotypic but polyclonal proliferation of plasma cells that occurs in HIV-negative individuals. It is characterized by a proliferation of HHV8-positive plasmablasts within germinal centers of lymph nodes with an otherwise intact
7
nodal architecture. Unlike MCD microlymphomas, co-infection with EBV is frequently present.40,41 The aggregates of germinotropic plasmablasts are negative for CD20, CD27, CD79a, CD138, BCL6, and CD10, but express IL-6, and are positive for HHV8-LANA1 and Epstein Barr-encoded RNA in situ hybridization (EBER).40 These cases are may be monotypic for either kappa or lambda light chains, but polyclonal by immunoglobulin gene rearrangement studies. Unlike the "microlymphomas" of MCD, these cases are not restricted in immunoglobulin subtype to IgM.36
Large B-cell lymphoma arising in HHV8-associated Multicentric Castleman Disease
Large B-cell lymphoma arising in association with MCD (LBCL-MCD), also known as HHV8positive plasmablastic lymphoma, is a subtype of large cell lymphoma that arises in patients with previous diagnosis of MCD, or in lymph nodes with a background suggestive of MCD.42 Although more frequently seen in AIDS patients, HIV-negative patients that develop endemic KS or MCD are also at risk of developing this type of lymphoma.42
MCD-LBCL is characterized by coalescent sheets of large plasmablasts that efface the nodal architecture. By immunohistochemistry, the plasmablasts are positive for HHV8-LANA1, IL-6, are variably positive for CD20, and are negative for CD79a and CD138. These cells are cytoplasmic IgM lambda-restricted, and are negative for EBV by EBER in situ hybridization. 35,42
Primary Effusion Lymphoma
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Primary effusion lymphoma (PEL), also known as body cavity-based lymphoma, is an uncommon subtype of large B-cell lymphoma strongly associated with HHV8 and EBV coinfection.3,4,43 It typically presents as lymphomatous effusions in the pleural, pericardial, or abdominal cavities of immunocompromised patients. Associated extracavitary masses are sometimes seen.2,43-45 However, isolated extracavitary presentations (termed solid variant or extracavitary PEL) are rare (see below).41 PEL is an aggressive tumor with a median survival of only 6 months.46
Morphologically, the neoplastic cells are large and often pleomorphic. In some cases, there is predominance of immunoblasts, and in others, there is more prominent anaplastic features, sometimes with scattered Reed-Sternberg-like cells. Finally, some cases show a range of plasmablastic and plasmacytoid cells with deep blue cytoplasm and perinuclear hofs.41
The neoplastic cells are positive for HHV8-LANA1, frequently express CD45, CD30, EMA, BCL-6, plasma cell markers CD138, CD38, MUM-1,47 and do not express surface immunoglobulin and B-cell markers CD19, CD20, CD79a, CD22, and PAX-5. While EBV infection can be demonstrated by EBER, expression of EBV- latent membrane protein-1 is usually absent.41 Few HHV8-negative or EBV-negative cases have been reported in the literature. 48,49
Genetic analyses have shown that PEL cells are most likely originated from post-germinal center B-cells, and as such, are usually hypermutated with clonal immunoglobulin gene
9
rearrangements.50 Of note, cases positive for both T-cell and B-cell gene rearrangements have been reported.51 The high cell proliferation has been linked to an abnormally stable c-Myc protein identified in PEL and associated with high expression of the HHV8- LANA1.52 This abnormally stable c-Myc is not associated with structural abnormalities of the c-MYC gene.51
Cases that are clinically and morphologically consistent with PEL, in which expression of T-cell markers, particularly, CD3, CD4, and/or CD5, are identified have been reported in the literature as T-cell primary effusion lymphoma.42,53,54 It is unclear whether such cases represent true HHV-8-positive T-cell lymphomas or a variant of PEL with aberrant T-cell expression.
Primary effusion lymphoma, solid (extracavitary) variant
The rare extracavitary variant of primary effusion lymphoma (E-PEL) is characterized by appearance of solid masses in the absence of effusions in AIDS patients.55,56 It has been reported in nodal and extranodal sites, specifically, oral cavity, gastrointestinal tract and skin.56,57 Extracavitary PEL is morphologically and phenotypically similar to classic PEL, albeit the more frequent expression of B-cell markers (CD20, CD79a, PAX-5 and surface immunoglobulins), reported in approximately 25% of E-PEL cases.53 Similar to the plasmablasts of MCD, the large neoplastic cells are monotypic IgM lambda.58 Compared to classic PEL, E-PEL is more likely to be negative for HHV8 or EBV in AIDS patients.55
This significant morphologic and phenotypic overlap of PEL/E-PEL with other plasmablastic types of lymphomas and myeloma can be diagnostically challenging in the absence of a clinical
10
history of immunosuppression/AIDS.59 In such instances, identification of EBV and HHV8 can be used to distinguish these neoplasms. In addition, there are reports of cases with anaplastic morphology misdiagnosed as Hodgkin lymphoma, due to the negative expression of CD20 and positive expression of CD30 and EMA.58,60 However, unlike classical Hodgkin lymphoma, anaplastic forms of PEL are usually positive for CD45 and negative for CD15.57
Other potential associations
There is a controversial association of HHV8 infection with inflammatory disorders such as sarcoidosis, systemic lupus erythematosus, pemphigus and Kikuchi lymphadenopathy, as well with multiple myeloma and bone marrow failure syndromes.8,61,62
Disease Mechanisms
Similar to other herpesviruses, the double-stranded DNA genome of HHV8 encodes for proteins that result in lytic and latent phases of infection.4,8,63,64 The predominant protein expressed during latency phase, LANA-1 promotes maintenance of the latent viral episome 4,62 through methylation of the HHV8 genome.65 The majority of tumor cells contain viral material in latent phase, and therefore do not produce HHV8 virions until the lytic phase when virions are shed from mucosal surfaces.8 Reactivation requires the presence of interferon gamma;15 however, the exact factors associated with the change form latent to lytic phase are not entirely understood.
11
HHV8 is capable of infecting B-cells, endothelial cells and epithelial cells,8 which may function as natural reservoirs for the virus in its latent phase. The ability of HHV8 to infect cells is extremely low, but may be enhanced by co-infection with HIV and/or EBV.7 This is supported by studies of KS that demonstrate that the mere presence of HHV8 coinfection is not sufficient to cause disease.66,67 Other studies suggest that the HIV transcription factor Tat augments the tumorigenesis effect of HHV8,66,67 thus providing another explanation for the strong association between HHV8 and HIV.
Many studies have characterized the role of immunosuppression in facilitating tumor formation in the setting of HHV8 infection. For example, an increased replication of HHV8 virions, demonstrated by the observation of increased serologic reactivity against the HHV8 lytic phase capsid protein Orf 65, is observed with a progressive decrease in the number of helper T-cells in HIV-positive patients.68
The oncogenic mechanisms of HHV-8 infection relate to its ability to promote cell survival and uncontrolled cell proliferation. This occurs through the release of cytokines and antiapoptotic proteins that are analogous to those of humans. One of the key genes in this process is Orf 74, which leads to an increased expression of viral antiapoptotic protein vBcl-2, a homologue to human Bcl-2. In addition to promoting cell survival, vBcl-2 expression induces the release of viral cytokines and growth factors that are human analogues.
One of the intriguing facets of these diseases is the recurring theme of lambda monotypia seen in MCD as well as PEL. Some studies have suggested that latent HHV8-infected cells are
12
disproportionately lambda over kappa, suggesting a predilection of the virus for lambda-positive cells. A transgenic mouse model induced to express the HHV8 gene, vFLIP, resulted in B-cells that were enriched for lambda-positive cells.36
Many of the symptoms of MCD are linked to the overproduction of serum HHV8 viral protein interleukin-6 (vIL-6), a homologue of the B-cell growth factor IL-6.69 The angiogenic and inflammatory properties of vIL-6 as well as its effect on the differentiation of B-cells to plasma cells are the mechanism for systemic symptoms and hypergammaglobulinemia that are characteristic of MCD. 70,71 In addition, the strong stimulatory effect of vIL-6 on B-cell/plasma cell differentiation is likely involved in the pathogenesis of the HHV8-positive lymphomas.72 However, the absence of increased IL-6 detection by immunohistochemistry or in situ hybridization in lymph nodes suggests that its effect on the pathogenesis of MCD may be qualitative rather than quantitative.73 Another growth factor seen in high levels in HHV8 infection is vascular endothelial growth factor (VEGF), which plays a role in proliferation of endothelial cells and, possibly, in the pathogenesis of KS.74
Diagnostic Methods
Serologic methods are widely used to diagnose exposure to HHV8. The most commonly used methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay (IFA), and Western blot, are designed to detect expression of HHV8 capsid proteins orf65 and orfK8.1.7 The reported sensitivity of these methods varies according to the study. This variation has been attributed to the intermittent viral protein expression related to changes in viral life cycle phases.
13
7
In a study of individuals with KS, sensitivity of immunologic assays can be increased to 93%
when antibodies targeting a combination of latent and lytic protein were used.75 PCR-based techniques to detect HHV8 DNA in sera, albeit highly specific, are limited by low sensitivities of less than 50%,73 particularly in the viral latent phase. Therefore, utilization of PCR in sera is regarded as inferior to serologic immunoassays.7
The specificity of serologic methods is influenced by cross-reactivity with other viral infectious agents, specifically, anti-EBV antibodies which cross-react with the HHV8 protein encoded by gene Orf 25.7 In tissue, immunohistochemistry or PCR can be used to demonstrate HHV8 infection, which is used to confirm the diagnosis of Kaposi sarcoma and the majority of HHV8 related lymphomas.
Conclusion
HHV8-related diseases are uncommon and encompass Kaposi sarcoma, aggressive types of large cell lymphomas, and reactive lymphadenopathies. The diagnosis of these entities is established based on recognition of characteristic morphologic and phenotypic findings in conjunction with the demonstration of HHV8, and in some cases EBV co-infection.
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51. Hollingsworth HC, Stetler-Stevenson M, Gagneten D, Kingma DW, Raffeld M, Jaffe ES. Immunodeficiency-associated malignant lymphoma. three cases showing genotypic evidence of both T- and B-cell lineages. Am J Surg Pathol. 1994;18(11):1092-1101.
52. Bubman D, Guasparri I, Cesarman E. Deregulation of c-myc in primary effusion lymphoma by kaposi's sarcoma herpesvirus latency-associated nuclear antigen. Oncogene. 2007;26(34):4979-4986.
53. Coupland SE, Charlotte F, Mansour G, Maloum K, Hummel M, Stein H. HHV-8-associated T-cell lymphoma in a lymph node with concurrent peritoneal effusion in an HIV-positive man. Am J Surg Pathol. 2005;29(5):647-652.
21
54. Wang H, Thorson JA. T-cell primary effusion lymphoma with pseudo-monoclonal rearrangements for immunoglobulin heavy chain. Blood. 2015;126(15):1856.
55. Chadburn A, Hyjek E, Mathew S, Cesarman E, Said J, Knowles DM. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol. 2004;28(11):1401-1416.
56. Deloose STP, Smit LA, Pals FT, Kersten M-, van Noesel, C J M, Pals ST. High incidence of kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma. Leukemia. 2005;19(5):851-855.
57. Cioc AM, Allen C, Kalmar JR, Suster S, Baiocchi R, Nuovo GJ. Oral plasmablastic lymphomas in AIDS patients are associated with human herpesvirus 8. Am J Surg Pathol. 2004;28(1):41-46.
58. Ferry JA, Sohani AR, Longtine JA, Schwartz RA, Harris NL. HHV8-positive, EBV-positive hodgkin lymphoma-like large B-cell lymphoma and HHV8-positive intravascular large B-cell lymphoma. Mod Pathol. 2009;22(5):618-626.
59. Ahn JS, Okal R, Vos JA, Smolkin M, Kanate AS, and Rosado FG. Plasmablastic lymphoma versus plasmablastic myeloma: An ongoing diagnostic dilemma. J Clin Pathol. In press.
60. Katano H, Suda T, Morishita Y, et al. Human herpesvirus 8-associated solid lymphomas that occur in AIDS patients take anaplastic large cell morphology. Mod Pathol. 2000;13(1):77-85.
61. Sun Y, Sun S, Li W, Li B, Li J. Prevalence of human herpesvirus 8 infection in systemic lupus erythematosus. Virol J. 2011;8:210. 22
62. Rosado FGN, Tang Y, Hasserjian RP, McClain CM, Wang B, Mosse CA. Kikuchi-fujimoto lymphadenitis: Role of parvovirus B-19, epstein-barr virus, human herpesvirus 6, and human herpesvirus 8. Hum Pathol. 2013;44(2):255-259.
63. Schulz TF. Epidemiology of kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. Adv Cancer Res. 1999;76:121-160.
64. Schulz TF. The pleiotropic effects of kaposi's sarcoma herpesvirus. J Pathol. 2006;208(2):187-198.
65. Chen J, Ueda K, Sakakibara S, et al. Activation of latent kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator. Proc Natl Acad Sci U S A. 2001;98(7):4119-4124.
66. Aoki Y, Tosato G. HIV-1 tat enhances kaposi sarcoma-associated herpesvirus (KSHV) infectivity. Blood. 2004;104(3):810-814.
67. Guo H, Pati S, Sadowska M, Charurat M, Reitz M. Tumorigenesis by human herpesvirus 8 vGPCR is accelerated by human immunodeficiency virus type 1 tat. J Virol. 2004;78(17):93369342.
68. Bennett NJ, May JS, Stevenson PG. Gamma-herpesvirus latency requires T cell evasion during episome maintenance. PLoS Biol. 2005;3(4):e120.
69. Uldrick TS, Wang V, O'Mahony D, et al. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with kaposi sarcoma-associated herpesvirus and HIV but without multicentric castleman disease. Clin Infect Dis. 2010;51(3):350-358. 23
70. Aoki Y, Jaffe ES, Chang Y, et al. Angiogenesis and hematopoiesis induced by kaposi's sarcoma-associated herpesvirus-encoded interleukin-6. Blood. 1999;93(12):4034-4043.
71. Brousset P, Cesarman E, Meggetto F, Lamant L, Delsol G. Colocalization of the viral interleukin-6 with latent nuclear antigen-1 of human herpesvirus-8 in endothelial spindle cells of kaposi's sarcoma and lymphoid cells of multicentric castleman's disease. Hum Pathol. 2001;32(1):95-100.
72. Samols MA, Skalsky RL, Maldonado AM, et al. Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog. 2007;3(5):e65.
73. Leger-Ravet MB, Peuchmaur M, Devergne O, et al. Interleukin-6 gene expression in castleman's disease. Blood. 1991;78(11):2923-2930.
74. Arastéh K, Hannah A. The role of vascular endothelial growth factor (VEGF) in AIDSrelated kaposi's sarcoma. Oncologist. 2000;5 Suppl 1:28-31.
75. Spira TJ, Lam L, Dollard SC, et al. Comparison of serologic assays and PCR for diagnosis of human herpesvirus 8 infection. J Clin Microbiol. 2000;38(6):2174-2180.
24
A
B
C
D
25
E
F
Figures A-F: (A) Kaposi sarcoma, tumor stage: interlacing fascicles of spindle cells (H&E, 200x magnification). (B) The spindled cells show nuclear staining with HHV8-LANA-1 immunohistochemical stain (200x magnification). (C) HHV8-negative plasma cell variant of Castleman disease: prominent interfollicular plasmacytosis, and a lymphoid follicle with involuted germinal center (H&E, 200x magnification). (D) HHV8-positive multicentric plasma cell variant of Castleman disease, with an aggregate of plasmablasts (microlymphoma) in the interfollicular area (H&E, 200x magnification). (E) Germinotropic lymphoproliferative disorder: clusters of plasmablasts expand the germinal center (H&E, 200x magnification). (F) Primary effusion lymphoma: numerous large pleomorphic cells with occasional plasmacytoid features (excentric nuclei and perinuclear hof) (H&E, 200x magnification).
26
Table 1 Summary of Clinicopathologic Features of HHV8-Related Diseases Clinical Presentation
Kaposi sarcoma
Violaceous cutaneous or mucosal lesions Patch, plaque, tumor stage.
Multicentric Castleman disease
B-symptoms, generalized lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia , cytopenias
HHV -8* +
+
EBV* * –
–
Morphology Variable number of spindle cells. Cohesive sheets in tumor stage. Interfollicular plasmacytosis with variable number of plasmablasts. Involuted germinal centers. Microlymphoma s (aggregates of plasmablasts) may be present.
Primary effusion lymphoma
Body cavity effusions with/out associated solid masses
+
+
Large cells with variable morphology (anaplastic, plasmablastic, plasmacytoid)
Extracavitary primary effusion lymphoma
Extranodal mass (oral mucosa, gastrointestinal tract, skin) and lymphadenopathy
+
+
Similar to primary effusion lymphoma
Germinotropic lymphoproliferativ e disorder
Localized lymphadenopathy
+
Aggregates of plasmablasts within germinal centers
-
Sheets of large cells with plasmablastic morphology, effacing the nodal architecture
Large cell lymphoma arising in HHV8associated multicentric Castleman disease.
Generalized lymphadenopathy and splenomegaly
+
+
Immunohistochemistr y Positive CD31, CD34, Factor VIII, actin, vWF, D2-40, FLI-1
CD138-positive plasma cells polytypic kappa/lambda, mixture of IgM, IgG and IgA
Large cells often positive CD45, CD138, CD30, EMA, MUM-1, bcl-6. Negative sIg, CD20, PAX-5, CD79a, LMP-1 Similar to primary effusion lymphoma; more likely to express Bcell markers and sIg. Negative CD20, CD79a, CD138, bcl-6, CD10, monotypic (polyclonal genetics) Variable CD20, negative CD138 and CD79a. Positive IL-6, and cIgM lambdarestricted.
* Positive by immunohistochemistry. ** Positive by in situ hybridization
27
Diseases: Disease
Matthew Auten, Annette S. Kim, Kyle T. Bradley, Flavia G. Rosado www.elsevier.com/locate/serndb
PII: DOI: Reference:
S0740-2570(17)30045-X http://dx.doi.org/10.1053/j.semdp.2017.04.004 YSDIA50506
To appear in: Seminars in Diagnostic Pathology Cite this article as: Matthew Auten, Annette S. Kim, Kyle T. Bradley and Flavia G. Rosado, Human Herpesvirus 8-Related Diseases: Histopathologic Diagnosis and Disease Mechanisms, Seminars in Diagnostic Pathology, http://dx.doi.org/10.1053/j.semdp.2017.04.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Human Herpesvirus 8-Related Diseases: Histopathologic Diagnosis and Disease Mechanisms
Matthew Autena1, Annette S. Kimb2, Kyle T. Bradleyc3, Flavia G. Rosadod* a
Department of Pathology, West Virginia University Department of Pathology, Brigham and Women's Hospital c Department of Pathology & Laboratory Medicine, Emory University Hospital, 1364 Clifton Rd NE, Atlanta, GA 30322 d Department of Pathology, West Virginia University, Address: 1 Medical Center Dr, Room 2146F/HSC North [email protected] [email protected] [email protected] [email protected] * Corresponding author. Phone: 304-293-0288; Fax: 304-293-1627. b
ABSTRACT The emergence of HIV/AIDS more than three decades ago led to an increased incidence of diseases caused by HHV8 co-infection, particularly Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Over time, the development of highly effective AIDS therapies has resulted in a decreased incidence of HHV8-associated entities, which are now more commonly found in patients with undiagnosed and/or untreated AIDS. Due to their rarity, some of these diseases may be difficult to recognize without appropriate clinical information. This article provides an overview of HHV8-related disorders, with a focus on their morphologic and phenotypic features, and includes a brief overview of laboratory methods used 1
Phone: 304-293-1621; Fax: 304 293 1627
2
Phone: 617-525-3172; Fax: 617-264-5169
3
Phone: 404-712-4066; Fax: 404-712-5596 1
to detect HHV8. Disease mechanisms by which the HHV8 virion promotes tumorigenesis are also reviewed.
Keywords: HHV8, AIDS, Kaposi, Primary effusion lymphoma, Castleman
[MANUSCRIPT] At the peak of the acquired immune deficiency syndrome (AIDS) epidemic, the analysis of samples of Kaposi sarcoma (KS) revealed a novel virus called Kaposi sarcoma-associated herpesvirus, currently known as human herpesvirus 8 (HHV8).1 Since its initial discovery, HHV8 infection has been linked to the pathogenesis of other neoplastic and non-neoplastic diseases, such as primary effusion lymphoma (PEL) and the plasma cell variant of Castleman disease. 1-3 Although more prevalent in the setting of AIDS, HHV8-related disorders also occur in human immunodeficiency virus (HIV)-negative individuals that are otherwise immunocompromised, e.g., due to immunosuppressive therapy or age-related immune senescence.4
Given their rarity and relatively non-descript morphologic features, the histopathologic diagnoses of HHV8 related diseases typically requires a high index of suspicion. A positive history of HIV infection is helpful but may not be known or available at the time of initial presentation. This review article provides an overview of HHV8-related diseases, with focus on the histopathologic diagnosis, ancillary diagnostic methods, and disease mechanisms.
2
Epidemiology
HHV8 was first described in 1994 as a herpesvirus homologous to Epstein-Barr virus (EBV).1 It belongs to the subfamily of gamma herpesviruses, and is the only member of the genus rhadinovirus known to infect humans.5
The prevalence of HHV8 infection varies widely according to geographic distribution, age, and behavioral groups, mirroring that of AIDS. It ranges from 1-25% in North America and Europe, 4,6,7
and is as high as 80% in Africa.4 In HIV-negative individuals, seroprevalence steadily
increases for each decade of life after 30 years of age.8 In adults, it is higher in homosexual individuals, drug abusers, and commercial sex workers.8
The route of transmission of HHV8 is largely unknown. HHV8 genetic material has been identified in variable proportions in oropharyngeal epithelium, saliva, semen, and blood, but the exact mechanism of transmission is not entirely understood. While the predominant form of transmission is sexual, the detection of HHV8 seroconversion in children suggests the existence of non-sexual routes. Although viral material has been detected in blood components, bloodborne transmission is rare.8
Although primary infections are likely asymptomatic in most cases, reported manifestations include febrile maculopapular rash in children,9 and a variety of non-specific symptoms such as fever, fatigue, lymphadenopathy, diarrhea, and cutaneous rash in adults.10 Severe forms of 3
primary infection, manifesting as bone marrow aplasia, fever and plasmacytosis, have been reported in organ transplant recipients.8
Clinical and Histopathologic Features HHV-8 infection is associated with Kaposi sarcoma, plasma cell variant of Castleman disease (more frequently the multicentric type), germinotropic lymphoproliferative disorder, primary effusion lymphoma (including extracavitary variant) and large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease. The clinical, morphologic and phenotypic features of these diseases are discussed below and summarized in Table 1 and Figures A-F. Kaposi Sarcoma Originally described in 1872,11 Kaposi sarcoma (KS) is a low grade neoplasm of HHV8-infected endothelial cells that arises in skin, lymph nodes, and gastrointestinal tract or other viscera, typically in elderly or immunocompromised patients.4 There are four epidemiologic forms of KS, all of which are histologically and phenotypically similar: (1) sporadic or classic, seen primarily in elderly men of Jewish or Mediterranean heritage; (2) endemic, seen in areas of central Africa; (3) iatrogenic, arising secondary to immunosuppressive therapy; and (4) AIDSrelated.12 Clinically, cutaneous KS tends to progress from early violaceous patches to more advanced lesions (plaques) and ultimately nodules (tumor).12 Other clinical variants described are infiltrative, ecchymotic, telangiectatic, keloidal, and cavernous/lymphangioma-like.13-17
4
Histologically, the cellular components of KS vary with the stage of disease.4 Patch lesions are defined by dermal proliferations of vascular spaces composed of irregular endothelial cells alongside normal capillaries. In plaques, the sheets or fascicles of spindle cells appear and begin to encircle the vascular space. Finally, in nodular lesions, the spindle cells predominate forming large fascicles.18
Immunohistochemical techniques using antibodies that target the HHV8 latency-associated nuclear antigen-1 (LANA-1) are positive in almost all cases,19 and are useful to confirm the diagnosis of KS. The tumor spindle cells express vascular markers CD31, CD34, FLI-1, FVIII, actin, von Willebrand factor, VEGRFR-3, and D2-40, regardless of HIV status.18,20,21 Highlyspecific PCR for HHV8 DNA sequences show a sensitivity of 86-100%, tending to be lower in classic KS compared to AIDS-related KS.22
Multicentric Castleman Disease Castleman disease, also known as angiofollicular lymphoid hyperplasia, was first described in 1956 by Benjamin Castleman, who studied biopsies from patients with bulky mediastinal lymphadenopathy.23,24 It is a heterogeneous group of inflammatory lymphadenopathies divided clinically into unicentric and multicentric variants based on the anatomic distribution of disease, and encompassing the hyaline-vascular and plasma cell morphologic variants.25 Unicentric disease typically corresponds to the hyaline-vascular morphologic variant whereas multicentric disease typically corresponds to the plasma cell variant, but the associations are imperfect.
5
Multicentric Castleman disease (MCD) is a syndrome characterized clinically by cyclic episodes of B-symptoms (fever, night sweats, and weight loss), hepatosplenomegaly, and lymphadenopathy, frequently abdominal or mediastinal. In some cases, skin rashes, body cavity effusions and neurologic symptoms are also seen.26-28 Common laboratory abnormalities include elevated erythrocyte sedimentation rate, anemia, thrombocytopenia, polyclonal hypergammaglobulinemia, hypoalbuminemia, elevated serum levels of IL-6, LDH, and Creactive protein.26-28
AIDS patients classically develop MCD,29 in which HHV8 DNA can be detected in nearly 100% of cases.30 There is high frequency of concurrent Kaposi sarcoma,30,31 and approximately 20% of these patients go on to develop primary effusion lymphoma or HHV8-positive large B-cell lymphoma.32 Despite the strong association of MCD and AIDS, HHV8 positivity is also seen in approximately 40% of AIDS-unrelated cases of MCD. In addition, HHV8-negative “idiopathic” forms of MCD have been recognized.33 Interestingly, HHV8-positive MCD is also associated with POEMS (P-polyneuropathy, O-organomegaly, E-endocrinopathy, M-monoclonal gammopathy, S- skin changes) syndrome.34
HHV8-positive cases of Castleman disease are usually plasma cell variant, which is morphologically characterized by variable degree of follicular involution, interfollicular vascular proliferation and polyclonal plasmacytosis, with a variable numbers of polyclonal plasmablasts.27 Plasmablasts, when present, are usually found in the mantle zones of the follicles, and it is these cells that are selectively infected with HHV8 and stain positive using LANA-1 immunohistochemistry. Cases with large number of plasmablasts have been named
6
“plasmablastic variant” in the literature.25 Nodules of plasmablasts in the interfollicular space or within germinal centers may develop as the disease progresses, and have been termed “microlymphomas.”35 In these cases a number of IgM lambda-restricted, HHV8-positive plasmablasts have been identified and are thought to represent an intermediate stage in the progression from MCD to frank HHV8-positive large B-cell lymphoma.35 Despite the lambda restriction of the plasmablasts, immunoglobulin gene rearrangement studies are polyclonal.36 In contrast, HHV8-negative forms of plasma cell variant of Castleman disease, tend to show a more mature proliferation of plasma cells that respect the mantle zones of the adjacent follicles. By immunohistochemistry, plasma cells can be highlighted with CD138 or CD79a, and the intact follicular architecture can be demonstrated by follicular dendritic cell markers such as CD21 or CD23. Plasma cells are polytypic with kappa and lambda, and comprise a mixture of heavy chains IgG, IgM and IgA.37
Patients with MCD are treated systemically with chemotherapy and steroids, and the prognosis is generally poor.38 In contrast, unicentric Castleman disease presents as localized lymphadenopathy in otherwise asymptomatic patients, and is usually successfully treated with surgical excision.39
Germinotropic lymphoproliferative disorder
Germinotropic lymphoproliferative disorder is a monotypic but polyclonal proliferation of plasma cells that occurs in HIV-negative individuals. It is characterized by a proliferation of HHV8-positive plasmablasts within germinal centers of lymph nodes with an otherwise intact
7
nodal architecture. Unlike MCD microlymphomas, co-infection with EBV is frequently present.40,41 The aggregates of germinotropic plasmablasts are negative for CD20, CD27, CD79a, CD138, BCL6, and CD10, but express IL-6, and are positive for HHV8-LANA1 and Epstein Barr-encoded RNA in situ hybridization (EBER).40 These cases are may be monotypic for either kappa or lambda light chains, but polyclonal by immunoglobulin gene rearrangement studies. Unlike the "microlymphomas" of MCD, these cases are not restricted in immunoglobulin subtype to IgM.36
Large B-cell lymphoma arising in HHV8-associated Multicentric Castleman Disease
Large B-cell lymphoma arising in association with MCD (LBCL-MCD), also known as HHV8positive plasmablastic lymphoma, is a subtype of large cell lymphoma that arises in patients with previous diagnosis of MCD, or in lymph nodes with a background suggestive of MCD.42 Although more frequently seen in AIDS patients, HIV-negative patients that develop endemic KS or MCD are also at risk of developing this type of lymphoma.42
MCD-LBCL is characterized by coalescent sheets of large plasmablasts that efface the nodal architecture. By immunohistochemistry, the plasmablasts are positive for HHV8-LANA1, IL-6, are variably positive for CD20, and are negative for CD79a and CD138. These cells are cytoplasmic IgM lambda-restricted, and are negative for EBV by EBER in situ hybridization. 35,42
Primary Effusion Lymphoma
8
Primary effusion lymphoma (PEL), also known as body cavity-based lymphoma, is an uncommon subtype of large B-cell lymphoma strongly associated with HHV8 and EBV coinfection.3,4,43 It typically presents as lymphomatous effusions in the pleural, pericardial, or abdominal cavities of immunocompromised patients. Associated extracavitary masses are sometimes seen.2,43-45 However, isolated extracavitary presentations (termed solid variant or extracavitary PEL) are rare (see below).41 PEL is an aggressive tumor with a median survival of only 6 months.46
Morphologically, the neoplastic cells are large and often pleomorphic. In some cases, there is predominance of immunoblasts, and in others, there is more prominent anaplastic features, sometimes with scattered Reed-Sternberg-like cells. Finally, some cases show a range of plasmablastic and plasmacytoid cells with deep blue cytoplasm and perinuclear hofs.41
The neoplastic cells are positive for HHV8-LANA1, frequently express CD45, CD30, EMA, BCL-6, plasma cell markers CD138, CD38, MUM-1,47 and do not express surface immunoglobulin and B-cell markers CD19, CD20, CD79a, CD22, and PAX-5. While EBV infection can be demonstrated by EBER, expression of EBV- latent membrane protein-1 is usually absent.41 Few HHV8-negative or EBV-negative cases have been reported in the literature. 48,49
Genetic analyses have shown that PEL cells are most likely originated from post-germinal center B-cells, and as such, are usually hypermutated with clonal immunoglobulin gene
9
rearrangements.50 Of note, cases positive for both T-cell and B-cell gene rearrangements have been reported.51 The high cell proliferation has been linked to an abnormally stable c-Myc protein identified in PEL and associated with high expression of the HHV8- LANA1.52 This abnormally stable c-Myc is not associated with structural abnormalities of the c-MYC gene.51
Cases that are clinically and morphologically consistent with PEL, in which expression of T-cell markers, particularly, CD3, CD4, and/or CD5, are identified have been reported in the literature as T-cell primary effusion lymphoma.42,53,54 It is unclear whether such cases represent true HHV-8-positive T-cell lymphomas or a variant of PEL with aberrant T-cell expression.
Primary effusion lymphoma, solid (extracavitary) variant
The rare extracavitary variant of primary effusion lymphoma (E-PEL) is characterized by appearance of solid masses in the absence of effusions in AIDS patients.55,56 It has been reported in nodal and extranodal sites, specifically, oral cavity, gastrointestinal tract and skin.56,57 Extracavitary PEL is morphologically and phenotypically similar to classic PEL, albeit the more frequent expression of B-cell markers (CD20, CD79a, PAX-5 and surface immunoglobulins), reported in approximately 25% of E-PEL cases.53 Similar to the plasmablasts of MCD, the large neoplastic cells are monotypic IgM lambda.58 Compared to classic PEL, E-PEL is more likely to be negative for HHV8 or EBV in AIDS patients.55
This significant morphologic and phenotypic overlap of PEL/E-PEL with other plasmablastic types of lymphomas and myeloma can be diagnostically challenging in the absence of a clinical
10
history of immunosuppression/AIDS.59 In such instances, identification of EBV and HHV8 can be used to distinguish these neoplasms. In addition, there are reports of cases with anaplastic morphology misdiagnosed as Hodgkin lymphoma, due to the negative expression of CD20 and positive expression of CD30 and EMA.58,60 However, unlike classical Hodgkin lymphoma, anaplastic forms of PEL are usually positive for CD45 and negative for CD15.57
Other potential associations
There is a controversial association of HHV8 infection with inflammatory disorders such as sarcoidosis, systemic lupus erythematosus, pemphigus and Kikuchi lymphadenopathy, as well with multiple myeloma and bone marrow failure syndromes.8,61,62
Disease Mechanisms
Similar to other herpesviruses, the double-stranded DNA genome of HHV8 encodes for proteins that result in lytic and latent phases of infection.4,8,63,64 The predominant protein expressed during latency phase, LANA-1 promotes maintenance of the latent viral episome 4,62 through methylation of the HHV8 genome.65 The majority of tumor cells contain viral material in latent phase, and therefore do not produce HHV8 virions until the lytic phase when virions are shed from mucosal surfaces.8 Reactivation requires the presence of interferon gamma;15 however, the exact factors associated with the change form latent to lytic phase are not entirely understood.
11
HHV8 is capable of infecting B-cells, endothelial cells and epithelial cells,8 which may function as natural reservoirs for the virus in its latent phase. The ability of HHV8 to infect cells is extremely low, but may be enhanced by co-infection with HIV and/or EBV.7 This is supported by studies of KS that demonstrate that the mere presence of HHV8 coinfection is not sufficient to cause disease.66,67 Other studies suggest that the HIV transcription factor Tat augments the tumorigenesis effect of HHV8,66,67 thus providing another explanation for the strong association between HHV8 and HIV.
Many studies have characterized the role of immunosuppression in facilitating tumor formation in the setting of HHV8 infection. For example, an increased replication of HHV8 virions, demonstrated by the observation of increased serologic reactivity against the HHV8 lytic phase capsid protein Orf 65, is observed with a progressive decrease in the number of helper T-cells in HIV-positive patients.68
The oncogenic mechanisms of HHV-8 infection relate to its ability to promote cell survival and uncontrolled cell proliferation. This occurs through the release of cytokines and antiapoptotic proteins that are analogous to those of humans. One of the key genes in this process is Orf 74, which leads to an increased expression of viral antiapoptotic protein vBcl-2, a homologue to human Bcl-2. In addition to promoting cell survival, vBcl-2 expression induces the release of viral cytokines and growth factors that are human analogues.
One of the intriguing facets of these diseases is the recurring theme of lambda monotypia seen in MCD as well as PEL. Some studies have suggested that latent HHV8-infected cells are
12
disproportionately lambda over kappa, suggesting a predilection of the virus for lambda-positive cells. A transgenic mouse model induced to express the HHV8 gene, vFLIP, resulted in B-cells that were enriched for lambda-positive cells.36
Many of the symptoms of MCD are linked to the overproduction of serum HHV8 viral protein interleukin-6 (vIL-6), a homologue of the B-cell growth factor IL-6.69 The angiogenic and inflammatory properties of vIL-6 as well as its effect on the differentiation of B-cells to plasma cells are the mechanism for systemic symptoms and hypergammaglobulinemia that are characteristic of MCD. 70,71 In addition, the strong stimulatory effect of vIL-6 on B-cell/plasma cell differentiation is likely involved in the pathogenesis of the HHV8-positive lymphomas.72 However, the absence of increased IL-6 detection by immunohistochemistry or in situ hybridization in lymph nodes suggests that its effect on the pathogenesis of MCD may be qualitative rather than quantitative.73 Another growth factor seen in high levels in HHV8 infection is vascular endothelial growth factor (VEGF), which plays a role in proliferation of endothelial cells and, possibly, in the pathogenesis of KS.74
Diagnostic Methods
Serologic methods are widely used to diagnose exposure to HHV8. The most commonly used methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay (IFA), and Western blot, are designed to detect expression of HHV8 capsid proteins orf65 and orfK8.1.7 The reported sensitivity of these methods varies according to the study. This variation has been attributed to the intermittent viral protein expression related to changes in viral life cycle phases.
13
7
In a study of individuals with KS, sensitivity of immunologic assays can be increased to 93%
when antibodies targeting a combination of latent and lytic protein were used.75 PCR-based techniques to detect HHV8 DNA in sera, albeit highly specific, are limited by low sensitivities of less than 50%,73 particularly in the viral latent phase. Therefore, utilization of PCR in sera is regarded as inferior to serologic immunoassays.7
The specificity of serologic methods is influenced by cross-reactivity with other viral infectious agents, specifically, anti-EBV antibodies which cross-react with the HHV8 protein encoded by gene Orf 25.7 In tissue, immunohistochemistry or PCR can be used to demonstrate HHV8 infection, which is used to confirm the diagnosis of Kaposi sarcoma and the majority of HHV8 related lymphomas.
Conclusion
HHV8-related diseases are uncommon and encompass Kaposi sarcoma, aggressive types of large cell lymphomas, and reactive lymphadenopathies. The diagnosis of these entities is established based on recognition of characteristic morphologic and phenotypic findings in conjunction with the demonstration of HHV8, and in some cases EBV co-infection.
14
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A
B
C
D
25
E
F
Figures A-F: (A) Kaposi sarcoma, tumor stage: interlacing fascicles of spindle cells (H&E, 200x magnification). (B) The spindled cells show nuclear staining with HHV8-LANA-1 immunohistochemical stain (200x magnification). (C) HHV8-negative plasma cell variant of Castleman disease: prominent interfollicular plasmacytosis, and a lymphoid follicle with involuted germinal center (H&E, 200x magnification). (D) HHV8-positive multicentric plasma cell variant of Castleman disease, with an aggregate of plasmablasts (microlymphoma) in the interfollicular area (H&E, 200x magnification). (E) Germinotropic lymphoproliferative disorder: clusters of plasmablasts expand the germinal center (H&E, 200x magnification). (F) Primary effusion lymphoma: numerous large pleomorphic cells with occasional plasmacytoid features (excentric nuclei and perinuclear hof) (H&E, 200x magnification).
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Table 1 Summary of Clinicopathologic Features of HHV8-Related Diseases Clinical Presentation
Kaposi sarcoma
Violaceous cutaneous or mucosal lesions Patch, plaque, tumor stage.
Multicentric Castleman disease
B-symptoms, generalized lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia , cytopenias
HHV -8* +
+
EBV* * –
–
Morphology Variable number of spindle cells. Cohesive sheets in tumor stage. Interfollicular plasmacytosis with variable number of plasmablasts. Involuted germinal centers. Microlymphoma s (aggregates of plasmablasts) may be present.
Primary effusion lymphoma
Body cavity effusions with/out associated solid masses
+
+
Large cells with variable morphology (anaplastic, plasmablastic, plasmacytoid)
Extracavitary primary effusion lymphoma
Extranodal mass (oral mucosa, gastrointestinal tract, skin) and lymphadenopathy
+
+
Similar to primary effusion lymphoma
Germinotropic lymphoproliferativ e disorder
Localized lymphadenopathy
+
Aggregates of plasmablasts within germinal centers
-
Sheets of large cells with plasmablastic morphology, effacing the nodal architecture
Large cell lymphoma arising in HHV8associated multicentric Castleman disease.
Generalized lymphadenopathy and splenomegaly
+
+
Immunohistochemistr y Positive CD31, CD34, Factor VIII, actin, vWF, D2-40, FLI-1
CD138-positive plasma cells polytypic kappa/lambda, mixture of IgM, IgG and IgA
Large cells often positive CD45, CD138, CD30, EMA, MUM-1, bcl-6. Negative sIg, CD20, PAX-5, CD79a, LMP-1 Similar to primary effusion lymphoma; more likely to express Bcell markers and sIg. Negative CD20, CD79a, CD138, bcl-6, CD10, monotypic (polyclonal genetics) Variable CD20, negative CD138 and CD79a. Positive IL-6, and cIgM lambdarestricted.
* Positive by immunohistochemistry. ** Positive by in situ hybridization
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